INTERVIEW WITH DR. MARK PEGRAM

DR. LOVE: I'm almost afraid to ask you this next question, but, actually, this came up at one of the case sessions here at San Antonio yesterday - 40-year-old woman, 11- positive nodes, strongly HER2-positive.

DR. PEGRAM: Don't ask me that question. (Laughter) I've seen that sort of patient treated in every imaginable way that you can consider. There's no right or wrong answer. I still see these patients occasionally being transplanted. I certainly occasionally see these patients treated with Herceptin. I would not be surprised if Herceptin is not going to be the way to go in such patients. I think that there's a very strong chance that the Herceptin adjuvant trials will be positive studies. The reason I say that with some conviction is that if you look historically at therapies that prolong survival in metastatic breast cancer, across the board, all of those drugs have had even greater benefits in the adjuvant setting.
So, technically, if you look at the 10 or more node-positive subgroup, they behave similarly to metastatic breast cancer. In fact, it is metastatic breast cancer. It's metastasized to the lymph nodes, which is the most common site of metastasis in this disease. So, there is strong scientific rationale for treating them with Herceptin. It's not the standard of care. We don't routinely do it, even at UCLA, for all of our patients. We usually look for a study that they qualify for first, we use it as our default, and we're lucky to be able to have that as our reflex, so we don't have to make the difficult decisions.

DR. LOVE: Let's talk about the studies that are out there right now, the ones that you are participating in, and the others that are out there that you find interesting and important. I guess a lot of them are really in the adjuvant setting. What are some of the ones that have you most excited and what are some of the ones that you hear being talked about in terms of the future?

DR. PEGRAM: Well, if we start with the adjuvant studies, we're really excited about the Breast Cancer International Research Group, Herceptin adjuvant trial. It's called 006. This is a study that is testing conventional chemotherapy strategies, that is, four cycles of AC followed by four cycles of Taxotere, to integration of Herceptin.
There are two strategies to integrate Herceptin with conventional chemotherapy. One is the, I'm going to call it the kind of a dummy approach, where we're just going to add it to conventional therapy, regardless of whether it makes the best sense or not. We do have an arm in that trial that is AC followed by Taxotere plus Herceptin. Now, we're concerned about that arm, because of the potential for cardiotoxicity of Herceptin in patients who have had recent Adriamycin exposure. For that reason, there's a very close scrutiny of that particular arm by a group consisting of two cardiologists, medical oncologists and other safety advisers. If there's any signal of cardiotoxicity that arm will drop out. The third arm, which we're most excited about, is the Taxotere-carboplatin-Herceptin arm, which is TCH. It is a non-anthracycline synergistic combination of active drugs that are synergistic. When you look at Taxotere-Herceptin there's synergy. When you look at carboplatin-Herceptin there's synergy. So, the three-drug combination is highly synergistic, and we don't have to worry as much about cardiotoxicity in that scenario.

DR. LOVE: How long is the Herceptin given?

DR. PEGRAM: It's given for one year in the BCIRG study.

DR. LOVE: In two arms?

DR. PEGRAM: That's correct.

DR. LOVE: And the third arm is what?

DR. PEGRAM: No Herceptin.

DR. LOVE: With which chemotherapy?

DR. PEGRAM: AC and Taxotere.

DR. LOVE: Okay.

DR. PEGRAM: There's one study being done in Europe where there's going to be a randomization between one year of adjuvant Herceptin and two years of adjuvant Herceptin. That's the only adjuvant study where the duration of Herceptin is a research question. In terms of metastatic breast cancer, we have a lot of exciting trials that we're very anxious to get results on. We just completed the Phase II Taxotere-platinum-Herceptin trials, and we just presented our data at the recent ECHO meeting in Lisbon. Both of those trials, 62 patients each, so a 124 patient experience now, the response rates were between 60-some percent and 80-some percent. And time to progression was between 12 and 17 months, which is really quite extraordinary. This was in the FISH-positive subset.
In fact, if you look at the time to progression analysis on both of those studies, with the TCH combination, the FISH-positive patients, despite their worse prognosis because of the HER2 gene alteration, are actually doing better than the HER2-negative patients treated with TCH. So, really, for the first time, we're starting to see a shift in the natural history of HER2-positive breast cancer, where the HER2-positives are doing better because of the synergistic Herceptin-based combinations. So, we think that's really exciting, and we think that's going to translate to maximum clinical benefit in the adjuvant trials.
Let me tell you about two other trials, which we're really excited about, that involve this TCH strategy. Both of these trials are in metastatic breast cancer. One is the BCIRG 007 trial, which is going to be a randomized study between Taxotere-Herceptin versus Taxotere-carboplatin-Herceptin. This will really test the platinum synergy hypothesis in metastatic breast cancer.
Nick Robert and Dennis Slamon have a study that's very similar to 007, which is nearing completion of its accrual now, which is Taxol-Herceptin versus Taxol-carboplatin-Herceptin. That study will be the first to reach its accrual goal to test the platinum synergy hypothesis. So, we're very excited about that trial. We don't have any results yet, but we anticipate results in the new year. We're very anxious and optimistic to really put this platinum synergy hypothesis to the test because, if it works, it'll add even more support for our adjuvant 006 TCH strategy.

DR. LOVE: Any reason to think there's a difference in Taxol or Taxotere in terms of synergy with Herceptin?

DR. PEGRAM: Oh, sure, there is. I mean, we've conducted a lot of experiments in our laboratory now, using a bank of HER2-positive breast cancer cell lines and, across the board, it looks like the Taxotere-Herceptin interaction is synergistic, and the Taxol-Herceptin interaction is less than synergistic. It's additive. So, that would give some credence to the concept of using Taxotere-Herceptin as the preferred taxane-Herceptin combination. All the studies that we're doing at UCLA that involve Herceptin-taxane combinations, apart from the U.S. Oncology-Robert study, which is just about to close. It's still open at UCLA, but after that closes we're moving on exclusively to Taxotere-Herceptin combinations.

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